Original article

Small molecule annotation for the Protein Data

Bank

Sanchayita Sen1 Jasmine Young2 John M Berrisford1 Minyu Chen3

Matthew J Conroy1 Shuchismita Dutta2 Luigi Di Costanzo2

Guanghua Gao2 Sutapa Ghosh2 Brian P Hudson2 Reiko Igarashi3

Yumiko Kengaku3 Yuhe Liang2 Ezra Peisach2 Irina Persikova2

Abhik Mukhopadhyay1 Buvaneswari Coimbatore Narayanan2

Gaurav Sahni1 Junko Sato3 Monica Sekharan2 Chenghua Shao2

Lihua Tan2 and Marina A Zhuravleva2

1Protein Data Bank in Europe (PDBe) EMBL-EBI Wellcome Trust Genome Campus Hinxton CB10 1SD

UK 2RCSB Protein Data Bank (RCSB PDB) Department of Chemistry and Chemical Biology Rutgers

University Piscataway NJ 08854-8087 USA and 3Protein Data Bank Japan (PDBj) Osaka University

Osaka Japan

Corresponding author Tel thorn441223494431 Fax thorn441223494468 Email ssenebiacuk

Citation details Sen S Young J Berrisford J M et al Small molecule annotation for the protein data bank

Database (2014) Vol 2014 article ID bau116 doi101093databasebau116

Received 28 September 2014 Revised 29 October 2014 Accepted 5 November 2014

Abstract

The Protein Data Bank (PDB) is the single global repository for three-dimensional struc-

tures of biological macromolecules and their complexes and its more than 100 000 struc-

tures contain more than 20 000 distinct ligands or small molecules bound to proteins and

nucleic acids Information about these small molecules and their interactions with pro-

teins and nucleic acids is crucial for our understanding of biochemical processes and

vital for structure-based drug design Small molecules present in a deposited structure

may be attached to a polymer or may occur as a separate non-covalently linked ligand

During curation of a newly deposited structure by wwPDB annotation staff each mol-

ecule is cross-referenced to the PDB Chemical Component Dictionary (CCD) If the mol-

ecule is new to the PDB a dictionary description is created for it The information about

all small molecule components found in the PDB is distributed via the ftp archive as an

external reference file Small molecule annotation in the PDB also includes information

about ligand-binding sites and about covalent and other linkages between ligands and

macromolecules During the remediation of the peptide-like antibiotics and inhibitors

present in the PDB archive in 2011 it became clear that additional annotation was

required for consistent representation of these molecules which are quite often com-

posed of several sequential subcomponents including modified amino acids and other

VC The Author(s) 2014 Published by Oxford University Press Page 1 of 11This is an Open Access article distributed under the terms of the Creative Commons Attribution License (httpcreativecommonsorglicensesby40) which permits

unrestricted reuse distribution and reproduction in any medium provided the original work is properly cited

(page number not for citation purposes)

Database 2014 1ndash11

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Original article

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chemical groups The connectivity information of the modified amino acids is necessary

for correct representation of these biologically interesting molecules The combined

information is made available via a new resource called the Biologically Interesting

molecules Reference Dictionary which is complementary to the CCD and is now

routinely used for annotation of peptide-like antibiotics and inhibitors

Introduction

The Protein Data Bank (PDB) is the single global repository

for three-dimensional (3D) structures of biological macro-

molecules and their complexes (1) The four partners of the

Worldwide PDB organization (wwPDB httpwwpdborg)

are the Research Collaboratory for Structural

Bioinformatics (RCSB PDB httprcsborg) (2) the PDB in

Europe (PDBe httppdbeorg) (3) the PDB Japan (PDBj

httppdbjorg) (4) and the Biological Magnetic Resonance

Bank (BMRB httpbmrbwiscedu) (5) They act as depos-

ition curation and distribution centres for PDB data

Although the PDB archive is focussed on macromolecules a

wide variety of small molecules are encountered bound to

proteins and nucleic acids Currently there are gt20 000 dis-

tinct kinds of small molecule present in the archive and

they are described in the wwPDB Chemical Component

Dictionary (CCD) These compounds include metals

ions cofactors fatty acids carbohydrates proteinogenic

(standard) and modified amino acids and nucleotides

chromophores antibiotics inhibitors and various other

compounds that may be naturally bound to a macromol-

ecule or acquired during purification or crystallization

The first step in ligand annotation by wwPDB curators

is to identify all the distinct chemical entities that are pre-

sent in a newly deposited structure including all polymers

and small molecules (6) PDB annotation is a complex sci-

entific process that requires understanding of the inter-

actions between small molecules and macromolecules

Aspects of small molecule annotation include

1 identifying small molecules in a newly deposited PDB

entry that are already present in the CCD

2 creating definitions for any small molecules that are

new to the PDB

3 geometry and stereochemistry validation

4 evaluating the fit of the model coordinates to the

experimental data

5 identifying any covalent links with other residues or

components

6 annotation of ligand binding sites and

7 extending or updating the annotation in Biologically

Interesting molecules Reference Dictionary (BIRD) for

peptide-like inhibitor and antibiotic molecules

The wwPDB CCD

The number of structures in the PDB archive has grown

from 7 in 1971 to gt100 000 in 2014 (7 8) All these struc-

tures are experimentally derived atomistic models of bio-

logically important proteins and nucleic acids from a huge

variety of organisms Many proteins in the PDB have sub-

strates co-factors reaction products or analogues of such

compounds bound to them In addition many proteins and

nucleic acids contain modified amino acid or nucleotide

residues Hence identifying monomeric components incor-

porated in the polymers and ligands is an important first

step of PDB annotation (6)

The chemical-component annotation of a PDB entry in-

volves identification of every small molecule that is present

in the structure either as part of a polymer or as a non-

covalently bound ligand With the increasing number of

structures in the PDB the number of unique chemical enti-

ties associated with them is increasing as well (Figure 1)

For annotation purposes it is important to identify and de-

scribe the chemical entities that are deposited to the PDB

in a systematic and consistent manner The wwPDB part-

ners achieved this through the creation of a chemical refer-

ence dictionary This contains the description of every

unique chemical entity which can then be reused in subse-

quent depositions that contain the same entity This dic-

tionary is known as the wwPDB CCD and currently

contains chemical definitions of more than 20 000 distinct

chemical entities

The wwPDB annotation software verifies for all small

molecules in a new deposition if they already occur in the

CCD When a small molecule in the deposited entry

matches an existing chemical definition in the CCD it is

assigned the same three-character identifier as in the CCD

The atom nomenclature of the small molecule in the entry

is updated to reflect the dictionary definition If a molecule

is new to the PDB then a dictionary description is created

for it The atomic coordinates from the deposited structure

are used for the initial deduction of the connectivity bond

orders and stereochemistry of the molecule In cases where

the small molecule has poor geometry extra annotation is

required to define the correct connectivity and bond

orders The dictionary definition for every molecule con-

tains both coordinates generated with idealized geometry

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and example experimental coordinates along with ma-

chine-readable chemical descriptors such as SMILES

strings (9) InChi (10) and InChi keys The CCD definition

also contains the systematic name synonyms chemical

formula formula weight and formal charge of the

molecule

The PDB uses PDB exchangemacromolecular

Crystallographic Information File format (PDBxmmCIF)

(11) to describe the contents of a PDB entry The advantages

of using mmCIF as the data model include its flexibility and

extensibility which allow addition of new data items to ad-

dress the ever-increasing size and complexity of deposited

structures The CCD is also maintained in CIF format (11)

and every chemical entity in the dictionary is assigned a

unique three-character identifier Each CCD entry contains

five CIF categories that provide the machine-readable chem-

ical description of the small molecule (Figure 2) The unique

three-character code assigned to a chemical component is

used as the primary key to connect the different categories

in the dictionary The _chem_comp category contains the

name synonyms chemical formula formula weight and

formal charge of the molecule along with some information

about the parent PDB entry which was used to construct

the dictionary entry For entities such as chromophores and

modified amino acids and nucleic acids the data

item_chem_compmon_nstd_parent_comp_id provides

information about the lsquoparentrsquo of the compound For ex-

ample the amino acid phosphotyrosine is derived from tyro-

sine which is therefore its parent The chromophore CRO

present in green fluorescent protein is derived from the

tripeptide Ser-Tyr-Gly Hence the dictionary definition of

CRO has Ser-Tyr-Gly listed as the parent of this chromo-

phore The _chem_comp category provides structural classi-

fication information about the compound The data items

_chem_comptype and _chem_comppdbx_type are used to

annotate the type and class of the molecule respectively A

standard or a sidechain modified L-amino acid is a member

of the class lsquoL-peptide linkingrsquo Amino acids and their modi-

fied forms occur in proteins and are designated as type

lsquoATOMPrsquo Sugars can be classified as lsquoD-saccharidersquo or lsquoL-

saccharidersquo depending on their configuration and they are

annotated as type lsquoATOMSrsquo

The _chem_comp_atom category contains atom-level

details about the compound This category not only

includes atom name element type aromaticity flag chiral-

ity and charge for every atom but also both the generated

and example experimental 3D coordinates for the entire

chemical entity Chemistry software CORINA (12) is used

to produce the programmatically generated conformation

The bond-order information is stored in the _chem_

comp_bond category whereas the SMILES and InChi

strings are in the _pdbx_chem_comp_descriptor category

Standard chemistry software such as from ACDlabs (http

wwwacdlabscom) CACTVS (13) and OpenEye (14) is

used to generate the systematic name SMILES and InChI

descriptors for the compound As part of a wwPDB collab-

oration with the Cambridge Crystallography Data Centre

Cambridge Structural Database (CSD) coordinates for

those small molecules in the PDB that also exist in CSD

will be included in the future as well

Figure 1 Number of new PDB chemical entity definitions created annually between 2000 and 2013

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The wwPDB annotation guidelines require the CCD

definition to pertain to the neutral unbound form of every

compound In cases where a new chemical entity is cova-

lently linked to another small molecule or to a polymer a

leaving atom (usually an oxygen atom labelled as OXT) is

introduced in the chemical definition of the compound In

this way the newly built chemical definition can be reused

in future depositions where the same compound may occur

either in covalently bound form or as a lsquofreersquo ligand The

use of leaving atoms to capture multiple chemical forms of

the same compound is especially common for amino acids

nucleotides and carbohydrates (Figures 3 and 4)

Annotation of ligand-binding sites

Covalently linked ligands are quite common in the PDB

including co-factors such as pyridoxal phosphate and

carbohydrates such as N-acetylglucosamine Non-covalently

linked ligands are usually bound to one or more polymers

through H-bonding ionic and van der Waals interactions

Some ligands are instrumental to the biological function of a

biomacromolecule or complex Obviously the binding en-

vironment of a ligand is important to stabilize a particular

conformational state that facilitates its biological function

The site-delineation software used in PDB annotation is

derived from the CCP4 (15) program CONTACT (http

wwwccp4acukhtmlcontacthtml) It determines which

polymeric residues make up the binding site for each non-

polymeric ligand present in the structure (Figure 5) using a

cut-off distance of 37 A from any atom of the ligand and

taking crystallographic symmetry into account For oligo-

saccharides and peptide-like inhibitors and antibiotics the

software generates binding-site information for the entire

molecule instead of for the individual moieties (Figure 6) In

addition to the software-generated site information any

author-provided details about catalytic site residues in a

protein are also included in the annotated entry In the

mmCIF file for a given entry the CIF categories _struct_site

Figure 2 Abbreviated category relationship diagram for the key CIF categories that are used in the CCD Three major categories _chem_comp

_chem_comp_bond and _chem_comp_atom are joined together to generate the machine readable dictionary description of the chemical entity The

unique three character code assigned to every new chemical entity acts as the primary key in the _chem_comp categoryid (coloured in purple) and is

used to connect the other categories (_chem_comp_bondcomp_id and _chem_comp_atomcomp_id)

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nloaded from

and _struct_site_gen contain the site information for all the

ligands present in the structure The struct_site category

contains residue-level information Each binding site is

identified using a unique alphanumeric identifier (AC1

AC2 ZZ9) which serves as the primary key for the

_struct_site category The _struct_site_gen category contains

information about all the neighbouring residues within

37 A of any atom of the ligand The data item _struct_site_

gensite_id is directly inherited from the struct_siteid of the

_struct_site category (Figure 7) In addition to the binding-

site annotation all covalent bonds between ligands and

polymeric residues or other ligands are annotated as cova-

lent linkages in the _struct_conn category of the PDBx

mmCIF file

In protein and DNA structures metal ions are often

found in coordination complexes with other molecules or

ions The metals or metal clusters present in metallopro-

teins such as haemoglobins transferrins cytochromes

nitrogenases and hydrogenases are bound to nitrogen sul-

phur or oxygen atoms belonging to protein residues The

details of the bond angles for each of these coordinated

metal centres are listed in REMARK 620 of the PDB file

(Figure 8) or the _pdbx_struct_conn_angle category of the

PDBxmmCIF file

Annotation of peptide-like inhibitors andantibiotics

In 2011 a major remediation was carried out by wwPDB

curators to improve the representation of peptide-like

inhibitors and antibiotics so that they can be more easily

identified and studied (16) Currently there are nearly

1300 such structures present in the PDB archive

The presence or absence of consecutive peptide bonds

determines how these molecules are represented in the

PDB If a peptide-like molecule contains two or more

consecutive peptide bonds it is annotated as a standard

polymer with information about recommended name

source organism and linkage information between the

amino acids and any non-standard residues present in the

molecule Cross-referencing to UniProt (17) for gene

products or to Norine (18) for non-ribosomal peptides is

attempted for such compounds

If the ligand has fewer than two consecutive peptide

bonds (examples of this include several PPACK

inhibitors and other peptide-like molecules) it is annotated

as a non-polymer like any other small molecule in

the CCD but with an identifiable subcomponent se-

quence running from amino terminal (N) to carboxy (C)

terminal

Antibiotics such as teicoplanin and vancomycin have

sugars or fatty acids attached to their peptide core Such

compounds are represented as a lsquogrouprsquo (16) which

includes the polymeric and non-polymeric constituents of

the antibiotic along with details about all the linkages

between them (Figure 9)

Figure 3 a-D-Glucose can form a(1ndash4) glycosidic linkages with other

carbohydrate molecules During the oligomerization process the O1

oxygen (highlighted in the figure) of the glucose is eliminated by the O4

oxygen of the other carbohydrate To account for this condensation re-

action the O1 oxygen of a-D-glucose (GLC) is annotated in the CCD as a

leaving atom The two-dimensional diagram in this figure is a copy of

the image from the RCSB PDB website (httprcsborgpdbligand

ligandsummarydohetIdfrac14GLC) It was generated using the ChemAxon

software (httpwwwchemaxoncom)

Figure 4 Seven a-D-glucose (GLC) molecules undergo condensation re-

action to form the circular oligosaccharide b-cyclodextrin [from PDB

entry 2v8l (30)]

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BIRD

The large amount of chemical and biological information

that emerged during the remediation of the peptide-like

antibiotic and inhibitor molecules in the PDB required sys-

tematic referencing and documenting for curation of future

depositions A new resource was created to assist the future

annotation of such compounds containing both chemical

and biological information The chemical information is

stored in Peptide Reference Dictionary (PRD) files

whereas the biological function is documented in a separ-

ate family file The chemical and biological information

are separately annotated so that chemically similar

Figure 5 Binding site for the Plk-2 inhibitor (7R)-8-cyclopentyl-7-ethyl-5-methyl-78-dihydropteridin-6(5H)-one (3 letter code 11 G) in PDB entry 4i6b

(31) The figure depicts the neighbouring residues that are within 37 A of the ligand 11 G

Figure 6 The environment for the oligosaccharide poly-N-acetylglucosamine (PNAG) is annotated instead of listing the environment of individual

sugars This avoids repeating the same sugar molecule in multiple binding sites

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molecules either with conserved core polymer sequence or

signature sequence motifs can be grouped under the same

family of antibiotics or peptide-like molecules For ex-

ample antibiotics such as chlorionectin A vancomycin

teicoplanin and balhimycin are part of the glycopeptide

antibiotic family For each chemically distinct peptide-like

molecule a new PRD description is created with a unique

identifier and information about its chemical composition

connectivity structural description (eg glycopeptide

anthracycline lipopeptide etc) and function (eg

immunosuppressant enzyme inhibitor thrombin inhibitor

etc) Information about a family of molecules is stored in

a FAM file which mainly includes biological annotation

(such as function mechanism of action and

Figure 7 Diagram showing the relationship between the_struct_site and _struct_site_gen categories used for annotation of ligand-binding sites The

_struct_site category holds information about the ligands that are present in the PDB entry and every ligand in this category is assigned a alphanu-

meric binding site identifier The _struct_site_gen category contains information of the residues that are present within the vicinity of the ligands

described in the struct_site category Both the categories are joined by the binding site identifier

Figure 8 Tetrahedrally coordinated Zn ion in entry 2VW4 (32) along with the annotation of the bond angles The REMARK 620 annotation indicates

the software calculated bond angle values between Zn A 503 and its surrounding residues The surrounding residues in anticlockwise direction are

Glu A 195 HisB 165 and Asp B 167 The sidechain carboxylate group of the Glu residue exists in two alternate conformation (A and B conformers)

The angle between GluA195B-Zn-HisB165 is 1178 GluA195B-Zn-Asp(OD1)B167 is 866 HisB165-Zn-Asp(OD1)B167 is 916 Glu195B-Zn-

ASP(OD2)B167 is 1052 HisB165-Zn-Asp(OD2)B167 is 1249 Asp(OD1)B167-Zn-Asp(OD2)B167 is 571 Glu(OE1)A195B-Zn-Glu(OE2)A195A is 241

HisB165-Zn- Glu(OE2)A195A is 1228 Asp(OD1)B167-Zn-Glu(OE2)A195A is 1093 and Asp(OD2)B167-Zn-Glu(OE2)A195A is 1107

Database Vol 2014 Article ID bau116 Page 7 of 11

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nloaded from

pharmacological action) and the list of family members in

the PRD (16) Remediated and newly released PDB entries

containing peptide-like compounds include PRD identifiers

in the PDBx files The new resource comprising both

chemical and biological information for these peptide-like

molecules is called the BIRD Both the PRD and family

files are distributed via the wwPDB ftp area (ftpftp

wwpdborgpubpdbdatabird) Currently there are nearly

200 families and more than 700 PRD entries in BIRD The

release of any new PRD entries or families is synchronized

with the release of the first PDB entry containing the cor-

responding peptide-like molecule

Figure 9 Annotation of the glycopeptide antibiotic teicoplanin involves lsquochopping uprsquo the molecule into its component chemical entities that are vali-

dated against the CCD The bonds highlighted in yellow demarcate the individual entities

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Validation of ligands in the PDB

The wwPDB structure validation process includes geometry

checks for all standard and non-standard amino acids and

nucleotides as well as carbohydrates and ligands Since

2008 wwPDB has convened several method-specific valid-

ation task forces (VTFs) composed of community experts

to provide recommendations on structure and data valid-

ation (19ndash21) The recommendations of the X-ray VTF

have been implemented in a software pipeline that is used

during deposition and annotation as a stand-alone server

and for validation of all legacy crystal structures in the arch-

ive (22) The validation pipeline uses a variety of external

and internal software To assess bond lengths bond angles

torsion angles and chirality for every small molecule present

in an entry use is made of the program Mogul (23) which

compares the geometry to that encountered in high-quality

small molecule structures in the CSD (24) The validation

pipeline also analyses the fit of ligands to the electron dens-

ity using approaches introduced by the Uppsala Electron-

Density Server (25) For every ligand in an entry the local

ligand density fit (LLDF) is calculated this is essentially a

Z-score of the ligandrsquos real space R-value (RSR) (26) relative

to the mean and standard deviation of the RSR values of the

neighbouring polymeric standard residues and nucleotides

(taking crystallographic symmetry into account) and using

a cut-off distance of 5 A from any ligand atom LLDF values

gt2 are highlighted in the report produced by the validation

pipeline (Figure 10) The validation report generated during

the annotation process is sent back to the depositor so it can

be included when a paper describing the structure is submit-

ted for publication Upon release of an entry the validation

pipeline is run on it again and the resulting report is made

publicly available

Conclusions and future directions

The PDB archive contains a wide variety of chemical enti-

ties many of which play a crucial role in modulating

biochemical reactions Correct identification and representa-

tion of these small molecules in the PDB at the annotation

stage is crucial to allow these molecules to be identified

compared etc by users Every structure deposited to the

PDB is dissected to identify the individual chemical entities

that are subsequently compared and validated against the

CCD When a chemical entity matches an existing diction-

ary entry it is assigned the same three-character identifier as

Figure 10 rA weighted 2Fo-Fc map of a carbohydrate binding protein shown at a contour level of 035eA^3 Very little electron density is observed

for the oligosaccharide molecule This is reflected in the high LLDF values (shown in parentheses) for each of the component carbohydrate moieties

Database Vol 2014 Article ID bau116 Page 9 of 11

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in the CCD In addition the nomenclature of the entityrsquos

atoms is updated to reflect the dictionary definition Once

the individual components have been correctly identified in-

formation is added about all the non-standard covalent H-

bonding and ionic interactions that occur in the structure

The annotation software also generates binding-site infor-

mation for every bound molecule For all crystal structures

symmetry information is taken into account during the iden-

tification of binding sites and non-covalent interactions

The rapid growth and increased complexity of the struc-

tures to PDB has prompted continuous review of the anno-

tation tools and processes used during processing and

handling the data deposited to the PDB To support the sci-

entific advancements in the field of structural biology the

wwPDB partners are collaborating to develop a new joint

deposition and annotation system (27) The new annotation

system contains four major modules such as a chemical

component module a sequence module a validation mod-

ule and a module for derived data The chemistry module

can perform simultaneous searches against both the CCD

and BIRD The new system has an interactive interface and

visualization tools that aid in annotation and facilitate cor-

rect representation of the data (28) The chemistry module

has been tested on previous depositions and has significantly

improved processing efficiency and data quality

AcknowledgementsThe 3D images in the manuscript were generated using PyMOL

(29) The authors are grateful to Prof Gerard Kleywegt for helpful

comments on this manuscript

Funding

PDBe is funded by EMBL-EBI Wellcome Trust (088944) BBSRC

(BBJ0074711 BBI02576X1 BBK0169701) RCSB is funded by

NSF NIH DOE (DBI-1338415) PDBj is funded by JST-NBDC

Institute for Protein Research IPR Osaka University The open

access fee for paper entitled lsquoSmall molecule annotation for the pro-

tein data bankrsquo will be paid by the Wellcome Trust Grant 088944

Conflict of interest None declared

References

1 BermanHM HenrickK KleywegtG et al (2012) The

Worldwide Protein Data Bank Int Tables Crystallogr F 827ndash832

2 RosePW BiC BluhmWF et al (2013) The RCSB Protein

Data Bank new resources for research and education Nucleic

Acids Res 41 D475ndashD482

3 GutmanasA AlhroubY BattleGM et al (2014) PDBe Protein

Data Bank in Europe Nucleic Acids Res 42 D285ndashD291

4 KinjoAR SuzukiH YamashitaR et al (2012) Protein Data

Bank Japan (PDBj) maintaining a structural data archive and re-

source description framework format Nulceic Acids Res 40

D453ndashD460

5 UlrichEL AkutsuH DoreleijersJF et al (2008)

BioMagResBank Nucleic Acids Res 36 D402ndashD408

6 DuttaS BurkhardtK YoungJ et al (2009) Data deposition

and annotation at the Worldwide Protein Data Bank Mol

Biotechnol 42 1ndash13

7 BermanHM KleywegtGJ NakamuraH et al (2013) How

community has shaped the Protein Data Bank Structure 21

1485ndash1491

8 Editorial (2014) Hard datamdashit has been no small feat for the

Protein Data Bank to stay relevant for 100000 structures

Nature 509 260

9 WeiningerD (1988) SMILES a chemical language and infor-

mation system 1 Introduction to methodology and encoding

rules J Chem Inf Model 28 31ndash36

10 HellerS McNaughtA SteinS et al (2013) InChImdashthe

worldwide chemical structure identifier standard

J Cheminform 5 7

11 BournePE BermanHM McMahonB et al (1997)

Macromolecular crystallographic information file Methods

Enzymol 277 571ndash590

12 GasteigerJ RudolphC and SadowskiJ (1990) Automatic gen-

eration of 3D-atomic coordinates for organic molecules

Tetrahedron Comp Method 3 537ndash547

13 IhlenfeldtWD TakahasiY AbeH et al (1992) CACTVS a

chemistry algorithm development environment In Machida K

Nishioka T (eds) Daijuukagakutouronkai Dainijuukai

Kouzoukasseisoukan Shinpojiumu Kouenyoushishuu Kyoto

University Press Kyoto pp 102ndash105

14 StahlM and MauserH (2005) Database clustering with a

combination of fingerprint and maximum common substructure

methods J Chem Inf Model 45 542ndash548

15 WinnMD BallardCC CowtanKD et al (2011) Overview

of the CCP4 suite and current developments Acta Crystallogr

D D67 235ndash242

16 DuttaS DimitropoulosD FengZ et al (2014) Improving the

representation of peptide-like inhibitor and antibiotic molecules

in the Protein Data Bank Biopolymers 101 659ndash668

17 The UniProt Consortium (2011) Reorganizing the protein space

at the Universal Protein Resource (UniProt) Nucleic Acids Res

40 D71ndashD75

18 CabocheS PupinM LeclereV et al (2008) NORINE a data-

base of nonribosomal peptides Nucleic Acids Res 36

D326ndashD331

19 ReadRJ AdamsPD ArendallWB et al (2011) A new gen-

eration of crystallographic validation tools for the Protein Data

Bank Structure 19 1395ndash1412

20 MontelioneGT NilgesM BaxA et al (2013)

Recommendations of the wwPDB NMR Structure Validation

Task Force Structure 21 1563ndash1570

21 HendersonR SaliA BakerML et al (2012) Outcome of the

first electron microscopy validation task force meeting

Structure 20 205ndash214

22 GoreS VelankarS and KleywegtGJ (2012) Implementing an

X-ray validation pipeline for the Protein Data Bank Acta

Crystallogr D68 478ndash483

23 BrunoIJ ColeJC KesslerM et al (2004) Retrieval of crys-

tallographically-derived molecular geometry information

J Chem Inf Model 44 2133ndash2144

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Dow

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24 AllenFH BellardS BriceMD et al (1979) The Cambridge

Crystallographic Data Centre computer-based search retrieval

analysis and display of information Acta Crystallogr B 35

2331ndash2339

25 KleywegtGJ HarrisMR ZouJY et al (2004) The

Uppsala Electron-Density Server Acta Crystallogr D 60 2240ndash2249

26 JonesTA ZouJY CowanSW et al (1991) Improved methods

for building protein models in electron density maps and the loca-

tion of errors in these models Acta Crytslallogr A 47 110ndash119

27 QuesadaM WestbrookJ OldfieldT et al (2011) The

wwPDB common tool for deposition and annotation Acta

Crystallogr A67 C403ndashC404

28 YoungJ FengZ DimitropolousD et al (2013) Chemical an-

notation of small and peptide-like molecules at the Protein Data

Bank Database 2013 1

29 The PyMOL Molecular Graphics System Version 12r3pre

Schrodinger LLC [Online]

30 TungJY ChangMD ChouWI et al (2008) Crystal struc-

tures of the starch-binding domain from Rhizopus oryzae

glucoamylase reveal a polysaccharide-binding path Biochem J

416 27ndash36

31 AubeleDL HomRK AdlerM et al (2013) Selective and

brain-permeable polo-like kinase-2 (Plk-2) inhibitors that reduce

alpha-synuclein phosphorylation in rat brain ChemMedChem

8 1295ndash1313

32 EllisMJ BuffeySG HoughMA et al (2008) On-line

optical and X-ray spectroscopies with crystallography an inte-

grated approach for determining metalloprotein structures in

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